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Atropisomerism about Aryl-Csp3 Bonds: Conformational Behavior of Substituted Phenylcyclohexanes in Solution Manon Flos, Pedro LAMEIRAS, Clement Denhez, Catherine Mirand, and Hatice BERBER J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02856 • Publication Date (Web): 23 Feb 2016 Downloaded from http://pubs.acs.org on February 28, 2016

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The Journal of Organic Chemistry

Atropisomerism about Aryl-Csp3 Bonds: Conformational Behavior of Substituted Phenylcyclohexanes in Solution Manon Flos,† Pedro Lameiras,‡ Clément Denhez,† Catherine Mirand,† and Hatice Berber*,† †

ICMR, CNRS UMR 7312, Université de Reims Champagne-Ardenne, Faculté de Pharmacie, 51 rue Cognacq-Jay, F-51096 Reims Cedex, France. ‡ICMR, CNRS UMR 7312, Université de Reims

Champagne-Ardenne, Moulin de la Housse, Bâtiment 18, BP 1039, F-51687 Reims Cedex 2, France. [email protected] RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)

A catalytic hydrogenation of cannabidiol derivatives phenylcyclohexenes was used to prepare epimeric (1R,1S) and/or rotameric (M,P) phenylcyclohexanes. The reaction is diastereoselective, in favor of 1SACS Paragon Plus Environment

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epimer, when large groups are attached to the phenyl ring. For each epimer, VT-NMR experiments including EXSY spectroscopy and DFT calculations were used to determine the activation energies of the conformational exchange arising from the restricted rotation about the aryl-Csp3 bond that lead to two unequally populated rotamers. The conformational preference arises essentially from steric interactions between substituents vicinal to the pivot bond. The conformers of epimers (1S)-2e,f show high rotational barriers of up to 92 kJmol-1, unlike to those of (1R)-2e,f with much lower barriers of about 72 kJmol-1. The height of the barriers not only depends on the substituents at the axis of chirality, but is also influenced by the position of a methyl group on the monoterpene ring. The feature most favorable to high rotational barriers is when the methyl at C1 lies equatorially. This additional substituent effect, highlighted for the first time, seems fundamental to allow or not atropisomerism in hindered ortho-substituted phenylcyclohexanes.

Introduction Atropisomerism is associated principally with single bonds that join a pair of hindered planar groups, and the ortho-substituted biaryl atropisomers are of course by far the most well-known.1 The resulting barrier to rotation is high enough to allow the isolation of conformational isomers. On the other hand, isolation of atropisomers originated from restricted rotation involving the tetrahedral carbon (about sp2sp3 and sp3-sp3 C-C bonds) has been an attractive subject to challenge chemists.1-4 A review on high rotational barriers in fluorene and triptycene derivatives has appeared first by Ǒki.2a Separation and isolation of stable atropisomers have also been reported in hindered aryl carbinols.3 Likewise, other atropisomers arising from the restricted rotation around aryl-Csp3 bonds have been isolated.4 These compounds usually have bulky substituents on the aromatic ring at ortho positions, or on the benzylic carbon, or both. Apart from these rare examples, isolation of atropisomers from such bonds is generally not possible. Moreover, Ǒki reported in 1990 that triptycene systems (with sp3-sp3 C-C bonds) can be used as probe for detection of intramolecular weak yet attractive interactions as population ratios of the rotamers.5 It ACS Paragon Plus Environment

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can detect weak n→σ* and n→π* charge-transfer interactions as well as interactions involving a methyl group that could not be found in other systems. In the case of C(sp2)-C(sp3) single bonds, π− π interaction influencing the conformation of aromatic rings in isolable atropisomers of 2-arylindoline derivatives has also been demonstrated.4a Recently, we reported the stereo-electronic origins of the rotational control around aryl-Csp3 bonds through theoretical calculations in ortho-substituted phenylcyclohexene and epoxide derivatives of cannabidiol and linderatin.6 We now report studies on the conformational behavior in phenylcyclohexane derivatives obtained by catalytic hydrogenation of the corresponding phenylcyclohexenes displayed in Scheme 1. Two major reasons motivated us for this: first, bioactive natural products having similar structures such as machaeridiols A, B7a and hydrogenated cannabidiol derivatives7b (Figure 1) attracted our attention seeing the importance of axial chirality recognized in drug discovery.8 Second, molecular mechanics simulation of the rotation about C(sp2)-C(sp3) bonds at the MM2 level predicted atropisomerism in phenylcyclohexanes with partial or full methyl substitution around the pivot bond.9 Figure 1. Structure of natural products and derivatives.

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Scheme 1. Structure of the Synthesized Compounds (2a-h)

Results and Discussion Synthesis of Phenylcyclohexane Diastereoisomers and Structure Determination by NMR. Eight phenylcyclohexanes 2a-h carrying diverse ortho groups were prepared (Scheme 1), with the aim of probing their potential for atropisomerism as previously done in phenylcyclohexenes 1a,b,f-h and their epoxide derivatives.6 Therefore, these derivatives were classified into three categories according to the nature of ortho substituents: 1) di-O-substituted compounds 2a,b with hydroxyl or ether/ester groups, 2) mono-O-substituted substrates 2c,d with hydroxyl or ester group in one side and a smaller hydrogen atom on the other side, and 3) bulky methyl,O-substituted derivatives 2e-h with hydroxyl, ether or esters groups. In this work, we study both the diastereoselectivity of the hydrogenation reaction and the possible conformational exchange or atropisomerism in obtained phenylcyclohexanes 2a-h by NMR experiments in solution. These compounds possess three stereogenic centers (C1, C3 and C4) with C1 generated, and a fourth element of chirality i.e. the axis of chirality along the Car-C3 bond that can lead to conformers at room temperature,10 as previously observed in ACS Paragon Plus Environment

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their corresponding epoxide derivatives.6 Consequently, the reaction could give complex mixtures of different diastereoisomers meaning two epimers 1R and 1S which can exist in turn as a mixture of two rotational diastereoisomers. In sum, four diastereoisomers (1R,M), (1R,P), (1S,M) and (1S,P) could be obtained in variable ratios. In order to assess the diastereoselectivity of the catalytic hydrogenation by reducing the number of the diastereoisomers to two epimers (1R and 1S), phenylcyclohexene 1i with a symmetrical aromatic moiety was selected (Scheme 2). Alkene 1i was hydrogenated to yield a mixture of epimers (1R)-2i and (1S)-2i in a ratio of 10:90, while epoxidation of 1i described in our previous study gives a single isomer.11 Catalytic hydrogenation is therefore less diastereoselective than epoxidation.6,11 However, hydrogenation occurs preferentially, as expected, on the less hindered face to give (1S)-2i as the major epimer. Scheme 2. Hydrogenation of 1i with Symmetrically Substituted Aromatic Ring

This result shows that hydrogenation of 1a-h with nonsymmetrical phenyl group could also give minor epimers (1R)-2a-h as a mixture of two conformers, which makes more difficult the structure analysis of each diastereoisomer. Compounds of the 1st group. Hydrogenation of alkenes 1a,b gave a mixture of two rotational diastereoisomers (1S,P)-2a,b and (1S,M)-2a,b (Schemes 1,3). In this group, the reaction is totally diastereoselective obtaining epimers (1S)-2a,b. To demonstrate the interconversion between the two conformers, (1S)-2b isomers were analyzed by VT-2D EXSY spectroscopy (Figure 2). In the EXSY spectrum at 338 K, chemical exchange occurs between two signals assigned to the C3-H protons of conformers (1S,P)-2b and (1S,M)-2b. VT 1H NMR experiments conducted on (1S)-2b conformers also


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confirm this conclusion by the coalescence of the two diastereomeric aromatic protons at 383 K in DMSO-d6 (see spectra in the Supporting Information). Scheme 3. Conformational Analysis of (1S)-2a,b

Figure 2. Expansion of the C3-H region of the 2D EXSY Spectrum (500 MHz, mixing time 0.2 s) of (1S)-2b in THF-d8 at 338 K.


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The structure of (1S,P)-2b and (1S,M)-2b obtained in a ratio of 40:60 in CDCl3 could be identified with the aid of the chemical shift difference for C3-H protons in the 1H NMR spectrum as previously observed in epoxide conformers.6 As indicated in Scheme 3, the C3-H proton is observed at 3.18 ppm in minor rotamer (1S,P)-2b and at 2.57 ppm in major rotamer (1S,M)-2b in CDCl3. This downfield shift, also observed in other solvents (see Table S1 in the Supporting Information), is caused by a deshielding effect of the oxygen lone-pair electrons of the ortho O-substituent in front of C3-H. This means that important electronic interactions exist between C3-H and the ortho group in front, and the stronger interaction occurs with OMe group in (1S,P)-2b with the most deshielded C3-H proton. NOESY experiments conducted on (1S)-2b conformers in DMSO-d6 are in agreement with these observations, and the significant correlations are specified in Scheme 3 (the full spectrum is in the Supporting Information). For rotamers (1S,P)-2a and (1S,M)-2a, obtained in a ratio of 46:54 in CD3OD, the C3-H chemical shifts are very close (2.98 and 3.07 ppm, respectively), which is not surprising in view of the similar nature of the substituents. Nonetheless, major rotamer (1S,M)-2b seems to have the most deshielded C3-H proton.


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Moreover, (1S)-2a conformers were converted into (1S)-2b conformers in two steps (Scheme 3). As expected, the same ratio of 40:60 in CDCl3 was found for conformers (1S,P)-2b and (1S,M)-2b, which confirms the structure of these diastereoisomers. Compounds of the 2nd group. Hydrogenation of mono-O-substituted phenylcyclohexenes 1c,d led to a mixture of two epimers (1R)-2c,d and (1S)-2c,d in ratios of 33:67 and 25:75, respectively (Schemes 1,4). The lack of correlation between the two signals corresponding to the C3-H protons in the NOESY/EXSY spectrum of 2d at 293 K in DMSO-d6 allowed us to identify unambiguously epimers(1R)-2d and (1S)-2d (Figure 3). In this family, the poor diastereoselectivity of hydrogenation can be explained by the fact that the phenyl ring is less substituted than in compounds 2a,b. Furthermore, conformational analysis in this group is more difficult as much as conformers are not detectable in CDCl3 at room temperature. Nevertheless, the EXSY spectrum displayed in Figure 3 also enabled us to highlight the presence of the very minor conformer of (1S)-2d (see also Figure S1 in the Supporting Information). These observations were verified by VT 1H NMR investigations on 2d (see spectra in the Supporting Information). The aromatic protons assigned to the very minor conformer of (1S)-2d were also detected at 293 K in DMSO-d6 and at 213 K in THF-d8. Scheme 4. Synthesis of 2c,d Epimers

3

3 1

RO

OR

H2, PtO2 cat EtOAc, rt 5 bars RO

1c R = H 1d R = Ac

1

+ OR O

O

3 1

RO

OR O

(1R)-2c : (1S)-2c (33 : 67) (1R)-2d : (1S)-2d (25 : 75)

Figure 3. Expansion of the C3-H region of the 2D EXSY/NOESY Spectrum (500 MHz, mixing time 0.6 s) of 2d in DMSO-d6 at 293 K.


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Compounds of the 3rd group. Hydrogenation of alkenes 1e-h gave a mixture of three diastereoisomers in 2e,f and a mixture of two rotational diastereoisomers in 2g,h (Schemes 1,5). Indeed, compounds 2e,f exist as a mixture of epimers (1R)-2e,f and (1S)-2e,f in ratios of 13:87 and 10:90, respectively; and epimers (1S)-2e,f turn out to be a mixture of two conformers (1S,P)-2e,f and (1S,M)2e,f in a ratio of 85:15 in CDCl3 in both cases. Hydrogenation of 1e,f is therefore not fully diastereoselective, unlike 1g,h obtained as a mixture of two conformers (1S,P)-2g,h and (1S,M)-2g,h in ratios of 84:16 and 70:30 in CDCl3, respectively. Consequently, the high diastereoselectivity of hydrogenation is significantly influenced by the presence of bulky substituents on the aromatic ring as observed in compounds (1S)-2a,b. Scheme 5. Synthesis of 2e-h Diastereoisomers


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3 1

OR

iPr

H2, PtO2 cat EtOAc, rt 5 bars

3 1

+

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CDCl3

3 1

iPr 3 1

OR OR (1R)

OR 1e R = H 1f R = Me 1g R = Ac 1h R = Piv

(1S,P)

(1S,M)

(1R)-2e : (1S)-2e (13 : 87); (1S,P)-2e : (1S,M)-2e (85 : 15) (1R)-2f : (1S)-2f (10 : 90); (1S,P)-2f : (1S,M)-2f (85 : 15) (1R)-2g : (1S)-2g (0 : 100); (1S,P)-2g : (1S,M)-2g (84 : 16) (1R)-2h : (1S)-2h (0 : 100); (1S,P)-2h : (1S,M)-2h (70 : 30)

Moreover, the presence in 2e,f at room temperature of both the minor epimer (1R) as a single compound and of the major epimer (1S) as a mixture of two conformers is intriguing insofar as the restricted rotation about the aryl-Csp3 bond should occur in the same way for both epimers. A mixture of four diastereoisomers should therefore be obtained. Separation of epimers (1S)-2e and (1R)-2e by chromatography (column and HPLC) was attempted in order to study their conformational process individually. For this reason, two other procedures of catalytic hydrogenation (variation of the pressure or change of catalyst) were employed to obtain a larger amount of minor epimer (1R)-2e (Table 1). For both procedures, epimeric ratios of about 30:70 (1R:1S) were obtained but with poor yields. Unfortunately, three spots with two of them very close to each other appear on TLC corresponding to 1R-epimer and the two atropisomers of 1S-epimer, which made difficult the isolation of each epimer.12 Nonetheless, efforts in separation by preparative TLC allowed us to collect an enriched fraction in epimer (1R)-2e with a ratio of 45:55 (1R:1S) whose the 1H NMR spectrum is shown in Figure 4b. Table 1. Two Other Procedures of Catalytic Hydrogenation Applied to 1e

Cat

Pressure

Yield in 2e

Epimeric ratio (1R)-2e : (1S)-2e[a]

Conformational ratio (1S,P)-2e : (1S,M)-2e[a]

PtO2

Atm (~1 bar)

38%

30 : 70

87 : 13


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Pd/C

The Journal of Organic Chemistry 5 bars

39%

30 : 70

87 : 13

[a] Ratios measured from the 1H NMR spectra in CDCl3.

In the 1H NMR spectra in CDCl3 at room temperature (Figure 4), a very broad signal for the benzylic C3-H proton is assigned to epimer (1R)-2e meaning that the rotation at the Car-C3 bond is restricted but not enough to observe conformers contrary to epimer (1S)-2e. These observations were demonstrated by VT NMR experiments (1H 1D and 2D-EXSY spectroscopy). The most significant results were obtained by exchange spectroscopy (Figure 5) which is better suited to the analysis of such complex mixtures than VT 1H NMR spectroscopy (see spectra in the Supporting Information). Figure 5 shows that the two conformers of (1R)-2e do interconvert at room temperature in DMSO-d6 and lower temperature (263 K) in THF-d8 while exchange occurs only at much higher temperature (393 K) in (1S)-2e atropisomers. Figure 4. 1H NMR spectra (300 MHz, CDCl3) of 2e at rt a) from PtO2 cat hydrogenation at 5 bars: dr (1R)-2e : (1S)-2e (13 : 87); b) from PtO2 cat hydrogenation at 1 bar after preparative TLC separation: dr (1R)-2e : (1S)-2e (45 : 55).


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Figure 5. Expansion of the C3-H region of the VT 2D EXSY Spectra of 2e at 500 MHz.


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In order to support these results, phenol 2e as a mixture of three diastereoisomers was also converted into its methyl ether 2f, acetate 2g and pivalate 2h (Scheme 6). As expected, the obtained 1R/1S epimeric ratios in 2f-h are similar to those of 2e, and the conformational ratios in CDCl3 in (1S,P)-2f-g and (1S,M)-2f-g come closer to those obtained from hydrogenation seen in Scheme 5. Scheme 6. Synthesis of 2f-h Diastereoisomers from 2e Diastereoisomers

The identity of atropisomers (1S,P)-2e-h and (1S,M)-2e-h was deduced by 1H NMR spectroscopy from the shielding/deshielding effect of the oxygen lone-pair electrons of one ortho substituent on the C3-H proton chemical shift as done in conformers of (1S)-2a,b. In the 1H NMR spectra in CDCl3, C3-H proton is observed at 2.73, 2.67, 2.73 and 2.72 ppm in major conformers (1S,P)-2e-h and at 3.28, 3.45, 2.83 and 2.88 ppm in minor conformers (1S,M)-2e-h, respectively (Figure 6). These observations are in agreement with NOESY experiments conducted on conformers of (1S)-2e also displayed in Figure 6 (see the NOESY spectrum in full in the Supporting Information). It is also noteworthy that, in each case, the P-conformer predominates. The rationale on the conformational preference is discussed below in the computational part. Figure 6. Conformational Analysis based on the the 1H NMR spectra of (1S)-2e-h in CDCl3 and on significant NOESY correlations in (1S)-2e in DMSO-d6 at rt. ACS Paragon Plus Environment

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Epimers (1R)-2e,f were obtained as single compounds in each case at room temperature in CDCl3. VTNMR experiments were then conducted at low temperature and two rotamers (P:M) become evident in a ratio of 90:10 at 233 K for (1R)-2e and 95:5 at 273 K for (1R)-2f in THF-d8, which is surprisingly diastereoselective (Figure 7). Here again, they could be identified by chemical shift variations of C3-H proton in the 1H NMR or 2D EXSY spectra. Figure 7. Conformational analysis based on the 1H NMR and 2D EXSY spectra of (1R)-2e,f at low temperature in THF-d8.


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The highlighted difference in the rotation rate about the Car-C3 bond between epimers (1R)-2e,f and (1S)-2e,f remains intriguing and, although quite away from the chiral axis, the methyl at C1 plays evidently an important role. These epimers differ only from each other by the position of the methyl group at C1 which is at axial in 1R-epimer and lies equatorially in 1S-epimer. Determination of Kinetic and Activation Parameters by VT-NMR Experiments. EXSY spectra can also be employed to measure rate constants of interconversions in the range from about 0.05 to 20 s-1.13 We were thus able to obtain rate constants of the aryl-Csp3 bond rotation in orthosubstituted phenylcyclohexanes (1S)-2b,e,f and (1R)-2e,f at low temperatures for 1R-epimers and at high temperatures for 1S-epimers.13b Activation parameters were then determined at 298 K from the Eyring plots of the corresponding rates of interconversion obtained by EXSY spectroscopy (Table 2, see also Table S3 and details in the Supporting Information). The highest bond rotation barriers (≥91 kJmol-1) were obtained for (1S)-2e,f atropisomers (Table 2, entries 2,4) bearing bulkier ortho methyl group in contrast to (1S)-2b rotamers (Table 2, entry 1) with lower barriers (≈85 kJmol-1). Furthermore, the difference in barriers to rotation between conformers of epimers (1R)-2e,f and (1S)2e,f is confirmed, but the obtained large value of around 20 kJmol-1 is very surprising. This huge difference in rotational barriers, only due to the position of the methyl at C1, may be attributed to the influence of the cyclohexane ring inversion on the interconversion around the indicated Car-C3 bond. The equatorial methyl in 1S-epimer conformers has less freedom to cyclohexane ring inversion unlike ACS Paragon Plus Environment

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the axial methyl in 1R-epimer conformers, which makes them less stable at this position so more flexible to conformational change. The position of the methyl group at C1 is therefore effective in raising or decreasing the rotational barriers in phenylcyclohexane conformers. Table 2. Activation Parameters of Phenylcyclohexane (1S)-2b,e,f and (1R)-2e,f Conformers at 298 K by VT 2D-EXSY Spectroscopy Entry

1

2

3

4

5

compd

(1S)-2b

(1S)-2e

(1R)-2e

(1S)-2f

(1R)-2f

k (s-1) [a,d]

∆G≠ (kJmol-1) [b,d]

t1/2 (s) [c,d]

k(P→M)

∆G≠(P→M)

t1/2(P→M)

k(M→P)

∆G≠(M→P)

t1/2(M→P)

0.009 ± 0.0005

84.6 ± 0.1

76 ± 4

0.008 ± 0.0008

85.1 ± 0.3

90 ± 10

0.0005 ± 0.00002

91.9 ±0.1

1434 ± 60

0.002 ± 0.0002

88.5 ± 0.2

364 ± 30

1 ± 0.7

72.4 ± 1.1

0.5 ± 0.3

11 ± 4

67.1 ± 0.8

0.06 ± 0.02

0.0007 ± 0.0001

91.1 ± 0.5

1038 ± 200

0.003 ± 0.0004

87.7 ± 0.4

263 ± 40

0.7 ± 0.03

73.8 ± 0.1

0.9 ± 0.04

8 ± 0.3

67.8 ± 0.1

0.09

±

0.004 [a] Rate constants at 298 K. [b] Free energies of activation for bond rotation at 298 K. [c] Half-lives for interconversion at 298 K. [d] Errors limits obtained from those reported for the slopes and intercepts in the Eyring plots.

The ∆Gc≠ were also determined for (1S)-2b,d,e,i and (1R)-2e conformers by VT 1H NMR experiments at coalescence temperatures from approximate equations14 displayed in Table 3 (see also Table S2, spectra and details in the Supporting Information). Although this method gives crude estimates of the rate of the aryl-Csp3 bond rotation in these rotamers, we found that the values match with those obtained by EXSY spectroscopy for (1S)-2b and (1R)-2e conformers even if they are slightly higher in (1S)-2b


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conformers and lower in (1R)-2e conformers. For (1S)-2e conformers, the values obtained from VT 1H NMR experiments are not reliable due to the fact that the only coalescing OH signal is not suited. Indeed, proton exchanges could also occur with the water present in the deuterated solvent (DMSO-d6) at high temperatures. To avoid this, another compound of the “third family” (1S)-2h with two distinct Har signals for the two atropisomers and without 1R-epimer was chosen to follow up VT 1H NMR studies. Remarkably, no coalescence of 1H NMR signals was observed up to 423 K in (1S)-2h atropisomers, which means that the barriers to rotation at coalescence are higher than at 298 K in these rotamers. Accordingly, barriers to bond rotation seem to increase slightly with the temperature as also observed in (1S)-2b and (1R)-2e conformers, and thus become temperature-dependent due to the sign of the entropy of activation. The discussion on the sign of ∆S≠ is further developed in the next part with the computed values. Regarding the second group of compounds, lower barriers of around 69 and 63 kJmol-1 were obtained for mono-O-substituted (1S)-2d conformers. Barriers decreased considerably over other di-orthosubstituted (1S)-phenylcyclohexanes ((1S)-2b,e,i) confirming the importance of the two ortho substituents. Table 3. Activation Parameters of Phenylcyclohexane (1S)-2b,d,e,i and (1R)-2e Conformers at Coalescence by VT 1H NMR Spectroscopy Entry

compd

Coalescing

Tc (K)[a]

signal

1

2

3

(1S)-2b

(1S)-2d

(1S)-2e

Har

Har

OH

383

303

408

kc (s-1)[b]

∆Gc≠ (kJmol-1)[c]

k(P→M)

∆G≠(P→M)

k(M→P)

∆G≠(M→P)

6

88.7

9

87.5

7

69.3

81

63.1

26

90.1


18

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4

5

(1R)-2e

(1S)-2i

OH

Har

288

378

145

84.2

11

64.6

101

59.5

84

83.8

[a] Coalescence temperature (±5 K). [b] Rate constants at Tc. [c] Free energies of activation (±0.5-1.2 kJmol-1) for bond rotation at Tc.

Computational Studies. DFT computation15 conducted on (1S)-2b,e,f and (1R)-2e,f also provided the thermodynamic and geometrical parameters of their conformers and transition states (Figure 8 and Table 4, see also Tables S4-S6 and details in the Supporting Information). Figure 8 shows the structures of the lowest-energy conformers and located transition states of epimers (1S)-2e and (1R)-2e, including their energetic barriers at 298 K. In (1S)-2e atropisomers, the computed values agree well with those determined by VT 2D EXSY experiments (Table 2, entry 2). In (1R)-2e conformers, the computed barriers, although slightly higher than those obtained experimentally, remain close to them (Table 2, entry 3). It is also noteworthy that there is a marked difference between the two TS structures (TS (1S)-2e and TS (1R)-2e) due to the position of the methyl group at C1, which should explain the large change in rotational barriers found experimentally. Regarding the cyclohexane moiety, a similar “boat” conformation characterizes the transition state structures in both epimers. However, a difference of almost 10° was calculated between C6-C5-C4-C3 dihedral angles of TS (1S)-2e and TS (1R)-2e (45.28° vs 32.68° displayed in Table S5 in the Supporting Information). This difference could be assumed by the position of the methyl at C1, which directly influences the energetic cost of the cyclohexane ring inversion. Indeed, in TS (1S)-2e the methyl at C1 and the substituted phenyl are axially on the same face of the cyclohexane ring and so interfere with each other, while only the phenyl is at axial in TS (1R)-2e. Therefore, the phenyl ring in TS (1R)-2e could easily rotate around the pivot bond unlike in TS (1S)-2e. Table 4 reports the complete computed thermodynamic parameters of one conformer in (1S)2b,e,f and (1R)-2e,f. As mentioned above, the theoretical barriers correlate reasonably with the ACS Paragon Plus Environment

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Page 20 of 32

experimental values. Table 4 shows also that ∆S≠ values are small, in the range of -22.3 to -35.1 Jmol1

K-1. Moreover, the negative sign of the entropies of activation, indicative of highly organized transition

states, is in accordance with the experimental results (see Table S3 in the Supporting Information).16 The influence of the temperature on the rotational barriers is therefore confirmed in these substrates. Figure 8. Structures and activated energies (kJmol-1) associated to the interconversion between (1S, P)2e and (1S, M)-2e through TS (1S)-2e (a), and between (1R, P)-2e and (1R, M)-2e through TS (1R)-2e (b) at the PCM/M06-2X/6-31G(d,p) level of theory.

Table 4. Theoretical Thermodynamic Parameters of (1S)-2b,e,f and (1R)-2e,f Conformers at 298 K Calculated at the PCM/M06-2X/6-31G(d,p) Level of Theory compd

∆H≠ (kJmol-1)

∆S≠ (Jmol-1K-1)

∆G≠ (kJmol-1)

(1S)-2b(M→P)

81.3

-26.7

89.3

(1S)-2e(P→M)

85.5

-26.1

93.3

(1R)-2e(P→M)

74.9

-28.6

83.5

(1S)-2f(P→M)

87.2

-22.3

93.8


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(1R)-2f(P→M)

79.1

-35.1

89.6

The identity of (1S)-2b,e,f and (1R)-2e,f conformers was also confirmed by computed 1H NMR chemical shifts of C3-H (see Table S7 in the Supporting Information). In order to explain the conformational control in these compounds, the second-order perturbation energy E(2) of donoracceptor interactions in the NBO basis was calculated for each conformer of (1S)-2b,e,f and (1R)-2e,f at the IEFPCM/M06-2X/6-31G(d,p) level of theory (Table 5). Interestingly, the main electronic stabilization by donor-acceptor charge transfer interactions (Olp → σ∗C3-H) is in favor of the minor conformers ((1S, P)-2b, (1S, M)-2e,f and (1R, M)-2e,f) according to the NBO analysis. Despite a tentative lowering of the energetic threshold in the NBO basis (from 2 to 0.4 kJmol-1), the sum of the amounts of the charge transfer between donor and acceptor is again in favor of the minor conformer in each case. It seems that the conformational equilibrium in these compounds is mainly driven by van der Waals interactions that counterbalance the favoring electronic interactions in the minor conformer. Nowadays, quantifications of van der Waals interactions constitute a challenge in modern quantum chemistry. However, the NCI approach (NCI plot software) allows us to visualize these interactions (see Figure S2 in the Supporting Information).17 Therefore, steric effects by van der Waals repulsion between the most bulky ortho group (acetyl or methyl) and the 2,4-diaxial C-H bonds could occur and destabilize these conformers despite the favoring electronic interactions. The conformational preference is thus mainly due to steric effects between substituents in close contact with each other on the two cycles. Likewise, these results could be extended to explain the stereoselectivity observed in the atropisomers of (1S)-2g,h. Notably, the best diastereoselectivity is attained in (1R)-2e,f conformers, followed by (1S)-2e,f atropisomers all bearing a hindered methyl group at ortho position. Table 5. NBO Values of E(2) (kJmol-1) and Relative Gibbs Free Energy (kJmol-1) for (1S)-2b,e,f and (1R)-2e,f Conformers at the IEFPCM/M06-2X/6-31G(d,p) Level of Theory compd

Olp → σ*C2-H

Olp → σ*C4-H

Olp → σ*C3-H

total

∆Gr°


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(1S, P)-2b

3.6

ND

6.6

10.2

(1S, M)-2b

2.1

4.6

2.9

9.6

(1S, P)-2e

ND

6.1

0.88 6.1 4.3 (1S, M)-2e (1R, P)-2e

7.5 ND

5.9

7.5 5.9 7.1

(1R, M)-2e (1S, P)-2f

8.2 ND

6.1

8.2 6.1 5.71

(1S, M)-2f (1R, P)-2f

7.5 ND

5.1

7.5 5.1 7.00

(1R, M)-2f

8.1

8.1

ND : not determined (< 2 kJmol-1).

Conclusion Some new cannabidiol and machaeridiol derivatives phenylcyclohexanes (2a-i) were synthesized by a catalytic hydrogenation as mixtures of two or three diastereoisomers. Spectroscopic NMR techniques were employed to analyze them and differentiate those originating from the pro-chiral center (C1) and those arising from the pro-chiral sp2-sp3 axis. The structures of each conformer in (1S)-2a-i and (1R)2e,f were determined by means of 1H NMR and/or 2D EXSY/NOESY spectra, and those for (1S)-2b,e,f and (1R)-2e,f were also confirmed by DFT computation, which also identified their transition structures. The NBO calculation was also applied to explain the conformational control in (1S)-2b,e,f and (1R)-2e,f conformers that is mainly due to steric interactions between the most hindered ortho group and two diaxial C-H bonds on the cyclohexane ring. Rotational barriers were determined either by VT 2D EXSY and VT 1H NMR methods in (1S)-2b,e,f and (1R)-2e,f conformers, which were reasonably in line with the computed data. Comparison of both methods showed that barriers increase slightly with the temperature. Mostly, we have demonstrated that atropisomerism is only reached with an equatorial methyl group at C1 and hindered ortho-substituents in phenylcyclohexane (1S)-2e-h atropisomers, while an axial methyl decreases significantly the rotational barriers (of about 20 kJmol-1) in the same ortho


22

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substituted (1R)-2e,f rotamers. The computed transition state for the interconversion of the conformers in each epimer rationalizes this rotational energetic difference. The height of the barriers to rotation about the pivot bond in phenylcyclohexanes is not only ortho-substituent-dependent, but is also influenced by the axial/equatorial positions of other substituents on the cyclohexane ring. Experimental Section General Experimental Methods. All reactions were performed under N2 atmosphere using ovendried glassware unless otherwise noted. All organic solvents and reagents were commercially available and used without further purification unless indicated otherwise. Reactions were monitored by thinlayer chromatography (TLC) using silica gel 60 covered alumina plates F254. TLC plates were viewed under UV light and stained using vanillin. Flash column chromatography was performed on silica gel (60A C.C 35-70 µm). Yields reported were for isolated, spectroscopically pure compounds which can exist as mixtures of diastereoisomers. 1H NMR and 13C NMR experiments were recorded on a 300 MHz instrument at ambient temperature unless otherwise noted. The residual solvent protons (1H) or the solvent carbons (13C) were used as internal standards. 1H NMR data are presented as follows: chemical shift in ppm downﬁeld from TMS (multiplicity, coupling constant, integration). The following abbreviations are used in reporting NMR data: s, singlet; br s, broad singlet; d, doublet; dd, doublet of doublets; t, triplet; q, quartet; m, multiplet. High and low mass spectra were recorded by electronic impact (EI) on a Mass Spectroscopy Quadripolar instrument (MSQ). Compounds 1a-i were described in the literature.6,11 General Procedure for Catalytic Hydrogenation of 1a-i. 1a-i and PtO2 (10%) in ethyl acetate were placed under 5 bars of H2 at rt. The reaction mixture was stirred for 24h. The catalyst was then removed by filtration, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give 2a-i as mixtures of diastereoisomers. For compounds 2e,f obtained as a mixture of three diastereoisomers ((1R)-2e,f, (1S,P)-2e,f and (1S,M)2e,f) and 2i as a mixture of two epimers ((1R)-2i, (1S)-2i), analytical data were described only for major (1S) diastereoisomers. ACS Paragon Plus Environment

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(P,M)-1-(2,4,6-Trihydroxy-3-((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)phenyl)ethanone (2a). mixture of two rotamers, 335 mg 95 %; amorphous solid: dr 46/54 (1S,P/1S,M); Rf = 0.24 (CH2Cl2/EtOAc, 96/4); 1H NMR (300 MHz, CD3OD) δ 5.87 (s, 0.46H), 5.83 (s, 0.54H), 3.07 (dt, J = 3.2 Hz, 11.5 Hz, 0.54H), 2.98 (dt, J = 3.2 Hz, J = 11.7 Hz, 0.46H), 2.59 (s, 1.38H), 2.58 (s, 1.62H), 2.18 (m, 1H), 1.85-1.58 (m, 3H), 1.55-1.32 (m, 3H), 1.11-0.90 (m, 2H), 0.86 (d, J = 6.4 Hz, 3H), 0.80 (d, J = 7.0 Hz, 3H), 0.66 (d, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CD3OD) δ 203.1 (C), 202.9 (C), 164.9 (C), 163.8 (C), 163.3 (C), 162.3 (C), 160.0 (C), 109.4 (C), 109.2 (C), 104.0 (C), 103.7 (C), 93.7 (CH), 93.1 (CH), 43.1 (CH), 42.8 (CH), 39.4 (CH2), 39.0 (CH2), 37.2 (CH), 36.7 (CH), 35.2 (CH2), 33.3 (CH), 31.4 (CH3), 31.3 (CH3), 28.1 (CH), 28.06 (CH), 24.9 (CH2), 21.5 (CH3), 20.5 (CH3), 14.7 (CH3), 14.6 (CH3); MS (EI) m/z (rel intensity, %) 306 (M+, 32), 221 (46), 181 (100), 95 (40); HRMS (EI-TOF) m/z calcd for C18H26O4 306.1831, found 306.1834. Anal. Calcd for C18H26O4: C, 70.56; H, 8.55. Found: C, 70.81; H, 8.75. (P,M)-2-Acetyl-6-((1S,2R,5S)-2-isopropyl-5-methycyclohexyl)-3,5-dimethoxyphenyl acetate (2b). mixture of two rotamers, 17 mg 20 %, liquid: dr 40/60 (1S,P/1S,M); Rf = 0.21 (petroleum ether/EtOAc, 90/10); 1H NMR (300 MHz, CDCl3) δ 6.35 (s, 0.4H), 6.34 (s, 0.6H), 3.86 (s, 1.2H), 3.853 (s, 1.8H), 3.85 (s, 3H), 3.18 (dt, J = 3.4 Hz, 11.6 Hz, 0.4H), 2.57 (ddd, J = 6.5 Hz, J = 8.8 Hz, J = 11.1 Hz, 0.6H), 2.47 (s, 1.2H), 2.46 (s, 1.8H), 2.25 (s, 1.8H), 2.23 (s, 1.2H), 2.04 (m, 0.6H), 1.85-1.62 (m, 2H), 1.611.51 (m, 2H), 1.50-1.30 (m, 2.4H), 1.21-0.89 (m, 2H), 0.88 (d, J = 6.0 Hz, 1.2H), 0.87 (d, J = 6.3 Hz, 1.8H), 0.81 (d, J = 7.0 Hz, 1.8H), 0.78 (d, J = 6.9 Hz, 1.2H), 0.64 (d, J = 6.9 Hz, 1.2H), 0.63 (d, J = 6.9 Hz, 1.8H); 13C NMR (75 MHz, CDCl3) δ 200.9 (C), 200.1 (C), 169.4 (C), 169.3 (C), 161.3 (C), 160.0 (C), 157.0 (C), 156.7 (C), 147.5 (C), 147.1 (C), 119.2 (C), 118.6 (C), 117.2 (C), 116.3 (C), 93.4 (CH), 92.6 (CH), 55.8 (CH3), 55.7 (CH3), 55.6 (CH3), 55.3 (CH3), 45.1 (CH), 43.6 (CH), 40.6 (CH2), 40.0 (CH), 39.4 (CH2), 37.3 (CH), 35.7 (CH2), 35.2 (CH2), 33.6 (CH), 33.5 (CH), 32.0 (CH3), 31.5 (CH3), 28.4 (CH), 28.1 (CH), 25.3 (CH2), 25.0 (CH2), 22.4 (CH3), 21.62 (CH3), 21.6 (CH3), 21.4 (CH3), 20.7 (CH3), 15.7 (CH3), 15.3 (CH3); MS (EI) m/z (rel intensity, %) 376 (M+, 14), 334 (40), 249 (56), 209


24

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(100); HRMS (EI-TOF) m/z calcd for C22H32O5 376.2250, found 376.2261. Anal. Calcd for C22H32O5: C, 70.19; H, 8.57. Found: C, 70.52; H, 8.81. (5SR)-1-(2,6-Dihydroxy-3-((1S,2R)-2-isopropyl-5-methylcyclohexyl)phenyl)ethanone

(2c).

mixture of two epimers, 63 mg 63%, liquid: dr 67/33 (1S/1R); Rf = 0.36 (petroleum ether/EtOAc, 90/10); 1H NMR (300 MHz, CDCl3) δ 12.4 (br s, 0.67H), 12.3 (br s, 0.33H), 7.14 (d, J = 8.3 Hz, 1H), 6.53 (br s, 1H), 6.28 (d, J = 8.6 Hz, 0.67H), 6.27 (d, J = 8.3 Hz, 0.33H), 3.12 (m, 0.33H), 2.96 (dt, J = 3.1 Hz, J = 11.3 Hz, 0.67H), 2.745 (s, 2.01H), 2.74 (s, 0.99H), 2.00 (m, 0.33H), 1.86-1.67 (m, 2.01H), 1.65-1.11 (m, 5.32H), 1.08 (d, J =7.2 Hz, 0.99H), 1.03-0.75 (m, 6.35H), 0.71-0.64 (m, 3H);

13

C NMR

(75 MHz, CDCl3) δ 205.9 (C), 161.0 (C), 160.7 (C), 156.9 (C), 134.7 (CH), 134.1 (CH), 125.8 (C), 109.8 (C), 106.5 (CH), 106.3 (CH), 47.2 (CH), 46.8 (CH), 44.5 (CH2), 40.8 (CH2), 34.0 (CH), 35.3 (CH2), 33.6 (CH3), 33.1 (CH), 31.9 (CH2), 28.1 (CH), 27.8 (CH), 27.6 (CH), 24.6 (CH2), 22.4 (CH3), 21.6 (CH3), 21.4 (CH3), 18.8 (CH2), 17.8 (CH3), 15.8 (CH3); MS (EI) m/z (rel intensity, %) 290 (M+, 43), 272 (12), 205 (59), 165 (100), 95 (25); HRMS (EI-TOF) m/z calcd for C18H26O3 290.1882, found 290.1888. (5SR)-2-Acetyl-4-((1S,2R)-2-isopropyl-5-methylcyclohexyl)-1,3-phenylene diacetate (2d). mixture of two epimers, 22 mg 100 %, liquid: dr 75/25 (1S/1R); Rf = 0.26 (petroleum ether/EtOAc, 90/10); 1H NMR (300 MHz, CDCl3) δ 7.31 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 8.7 Hz, 0.75H), 7.04 (d, J = 8.6 Hz, 0.25H), 2.83 (dt, J = 5.2 Hz, J = 10.6 Hz, 0.25H), 2.57 (dt, J = 3.1 Hz, J = 11.5 Hz, 0.75H), 2.45 (s, 3H), 2.28 (s, 6H), 2.03 (m, 0.25H), 1.88-1.65 (m, 2.25H), 1.60 (m, 0.5H), 1.58-1.33 (m, 3.75H), 1.18-0.93 (m, 3H), 0.93-0.76 (m, 5.25H), 0.69-0.61 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 199.3 (C), 169.0 (C), 168.8 (C), 168.6 (C), 145.1 (C), 145.0 (C), 136.9 (C), 129.4 (CH), 129.1 (CH), 127.7 (C), 120.6 (CH), 47.2 (CH), 47.0 (CH), 44.1 (CH2), 41.0 (CH), 39.6 (CH), 35.0 (CH2), 33.2 (CH), 31.9 (CH2), 31.1 (CH3), 27.7 (CH), 27.6 (CH), 27.5 (CH), 24.5 (CH2), 22.3 (CH3), 21.6 (CH3), 21.1 (CH3), 20.7 (CH3), 18.5 (CH2), 17.4 (CH3), 15.6 (CH3), 15.5 (CH3), 14.1 (CH3); MS (EI) m/z (rel intensity, %) 374 (M+, 3), 332 (38), 314 (2), 290 (100), 272 (20), 205 (34), 165 (61); HRMS (EI-TOF) m/z calcd for C22H30O5 374.2093, found 374.2105. ACS Paragon Plus Environment

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(P,M)-2-((1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl)-3,5-dimethylphenol (2e). mixture of two atropisomers, 362 mg 60 %, yellow liquid: dr 85/15 (1S,P/1S,M); Rf = 0.25 and 0.12 (petroleum ether/CH2Cl2, 90/10); HPLC (Silica, hexane/CH2Cl2, 90/10) tR(P) = 17.3 min and tR(M) = 21.4 min, dr 80/20, 1H NMR (300 MHz, CDCl3) δ 6.59 (s, 0.85H), 6.52 (s, 0.15H), 6.43 (s, 0.15H), 6.36 (s, 0.85H), 4.62 (br s, 1H), 3.28 (dt, J = 3.4 Hz, J = 11.9 Hz, 0.15H), 2.73 (dt, J = 4.5 Hz, J = 10.8 Hz, 0.85H), 2.38 (s, 0.45H), 2.31 (s, 2.55H), 2.23 (s, 3H), 2.17 (m, 0.85H), 1.88 (m, 0.15H), 1.85-1.67 (m, 2H), 1.67-1.33 (m, 4H), 1.15-0.93 (m, 2H), 0.92 (d, J = 6.1 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H), 0.68 (d, J = 6.9 Hz, 3H); 13

C NMR (75 MHz, CDCl3) δ 154.2 (C), 137.7 (C), 135.9 (C), 126.7 (C), 125.5 (CH), 124.1 (CH),

115.1 (CH), 113.9 (CH), 44.6 (CH), 44.5 (CH), 42.4 (CH), 40.3 (CH2), 40.1 (CH2), 39.2 (CH), 35.6 (CH2), 35.5 (CH2), 33.7 (CH), 28.3 (CH), 25.5 (CH2), 25.4 (CH2), 22.5 (CH3), 21.8 (CH3), 21.6 (CH3), 20.8 (CH3), 20.7 (CH3), 16.2 (CH3), 15.5 (CH3); MS (EI) m/z (rel intensity, %) 260 (M+, 55), 175 (80), 135 (100); HRMS (EI-TOF) m/z calcd for C18H28O 260.2140, found 260.2142. Anal. Calcd for C18H28O: C, 83.02; H, 10.84. Found: C, 82.68; H 11.18. (P,M)-2-((1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl)-1-methoxy-3,5-dimethylbenzene

(2f).

mixture of two atropisomers, 61 mg 92 %, liquid: dr 85/15 (1S,P/1S,M); Rf = 0.64 (petroleum ether); 1H NMR (300 MHz, CDCl3) δ 6.58 (s, 0.85H), 6.54 (s, 0.15H), 6.53 (s, 1H), 3.76 (s, 0.45H), 3.75 (s, 2.55H), 3.45 (dt, J =3.4 Hz, J = 11.7 Hz, 0.15H), 2.67 (ddd, J =5.5 Hz, J = 8.5 Hz, J = 10.8 Hz, 0.85H), 2.36 (s, 0.45H), 2.28 (s, 2.55H), 2.26 (s, 3H), 2.22 (m, 0.85H), 1.87 (m, 0.15H), 1.82-1.63 (m, 2H), 1.62-1.28 (m, 4H), 1.16-0.90 (m, 2H), 0.88 (d, J = 6.2 Hz, 3H), 0.83 (d, J = 6.9 Hz, 0.45H), 0.82 (d, J = 7.0 Hz, 2.55H), 0.64 (d, J =6.8 Hz, 0.45H), 0.63 (d, J = 6.9 Hz, 2.55H); 13C NMR (75 MHz, CDCl3) δ 158.6 (C), 137.1 (C), 135.5 (C), 129.0 (C), 125.1 (CH), 124.0 (CH), 110.4 (CH), 109.7 (CH), 55.9 (CH3), 55.0 (CH3), 44.5 (CH), 44.1 (CH), 43.0 (CH), 40.3 (CH2), 40.1 (CH2), 38.3 (CH), 35.65 (CH2), 35.6 (CH2), 33.8 (CH), 33.7 (CH), 28.3 (CH), 25.6 (CH2), 25.4 (CH2), 22.6 (CH3), 21.8 (CH3), 21.4 (CH3), 21.2 (CH3), 20.8 (CH3), 16.2 (CH3), 15.4 (CH3); MS (EI): m/z (rel intensity, %) 274 (M+, 55), 189 (100), 149 (86), 136 (36), 119 (38); HRMS (EI-TOF) m/z calcd for C19H30O 274.2297 found 274.2292. Anal. Calcd for C19H30O: C, 83.15; H, 11.02. Found: C, 83.61; H 11.10. ACS Paragon Plus Environment

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(P,M)-2-((1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl)-3,5-dimethylbenzene acetate (2g). mixture of two atropisomers, 49 mg 59 %, liquid: dr 84/16 (1S,P/1S,M); Rf = 0.28 (petroleum ether/CH2Cl2, 90/10); 1H NMR (300 MHz, CDCl3) δ 6.85 (s, 0.84H), 6.80 (s, 0.16H), 6.66 (s, 1H), 2.83 (dt, J = 3.4 Hz, J = 11.8 Hz, 0.16H), 2.73 (dt, J = 3.4 Hz, J = 11.7 Hz, 0.84H), 2.40 (s, 0.48H), 2.32 (s, 2.52H), 2.31 (s, 0.48H), 2.30 (s, 2.52H), 2.26 (s, 3H), 1.93-1.69 (m, 3H), 1.68-1.56 (m, 1H), 1.55-1.18 (m, 3H), 1.160.89 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H), 0.81 (d, J = 7.0 Hz, 3H), 0.65 (d, J = 6.8 Hz, 0.48H), 0.63 (d, J = 6.9 Hz, 2.52H);

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C NMR (75 MHz, CDCl3) δ 169.5(C), 149.0 (C), 137.8 (C), 135.7 (C), 131.7 (C),

130.9 (CH), 129.2 (CH), 122.1 (CH), 120.7 (CH), 45.2 (CH), 44.3 (CH), 42.4 (CH), 40.93 (CH), 40.9 (CH2), 35.8 (CH2), 35.4 (CH2), 35.2 (CH2), 33.9 (CH), 33.7 (CH), 28.0 (CH), 25.4 (CH2), 25.3 (CH2), 22.5 (CH3), 22.4 (CH3), 21.7 (CH3), 21.6 (CH3), 21.4 (CH3), 20.73 (CH3), 20.7 (CH3), 16.0 (CH3), 15.3 (CH3); MS (EI) m/z (rel intensity, %) 302 (M+, 14), 260 (100), 175 (80), 135 (100); HRMS (EI-TOF) m/z calcd for C20H30O2 302.2246, found 302.2253. Anal. Calcd for C20H30O2: C, 79.42; H, 9.997. Found: C, 79.02; H 10.17. (P,M)-2-((1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl)-3,5-dimethylbenzene pivalate (2h): mixture of two atropisomers, 112 mg 59 %, liquid: dr 70/30 (1S,P/1S,M); Rf = 0.28 (petroleum ether/CH2Cl2, 90/10); 1H NMR (300 MHz, CDCl3) δ 6.82 (s, 0.7H), 6.77 (s, 0.3H), 6.60 (s, 0.3H), 6.51 (s, 0.7H), 2.88 (dt, J = 3.3 Hz, J = 11.7 Hz, 0.3H), 2.72 (dt, J = 3.4 Hz, J = 11.6 Hz, 0.7H), 2.38 (s, 0.9H), 2.32 (s, 2.1H), 2.25 (s, 3H), 1.91 (m, 1H), 1.84-1.535 (m, 3H), 1.53-1.28 (m, 12H), 1.14-0.89 (m, 2H), 0.88 (d, J = 6.2 Hz, 2.1H), 0.84 (d, J = 7.0 Hz, 0.9H), 0.79 (d, J = 6.9 Hz, 3H), 0.66 (d, J = 6.8 Hz, 0.9H), 0.65 (d, J = 6.9 Hz, 2.1H); 13C NMR (75 MHz, CDCl3) δ 177.0 (C), 149.8 (C), 149.2 (C), 137.5 (C), 135.5 (C), 131.7 (C), 130.3 (CH), 128.6 (CH), 121.6 (CH), 120.5 (CH), 44.1 (CH), 42.1 (CH), 40.4 (CH), 40.1 (CH2), 39.8 (CH2), 35.3 (CH2), 35.1 (CH2), 33.6 (CH), 33.4 (CH), 29.5 (C), 29.2 (C), 27.7 (CH), 27.3 (3CH3), 27.1 (3CH3), 25.3 (CH2), 25.0 (CH2), 22.4 (CH3), 22.2 (CH3), 21.4 (CH3), 21.2 (CH3), 20.7 (CH3), 20.4 (CH3), 15.8 (CH3), 15.0 (CH3); MS (EI) m/z (rel intensity, %) 344 (M+, 47), 260 (100), 175 (72), 135 (100), 57 (51); HRMS (EI-TOF) m/z calcd for C23H36O2 344.2715, found 344.2719. Anal. Calcd for C23H36O2: C, 80.18; H 10.53. Found: C, 80.40; H 10.75. ACS Paragon Plus Environment

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2-((1S,2R,5S)-2-Isopropyl-5-methycyclohexyl)-1,3,5-trimethoxybenzene (2i). 70 mg, 70 %, liquid: Rf = 0.28 (petroleum ether/CH2Cl2, 90/10); 1H NMR (300 MHz, CDCl3) δ 6.13 (d, J = 2.4 Hz, 1H), 6.11 (d, J = 2.4 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 3.08 (dt, J = 3.7 Hz, J = 11.2 Hz, 1H), 2.02 (m, 1H), 1.83-1.28 (m, 6H), 1.11-0.89 (m, 2H), 0.87 (d, J = 6.2 Hz, 3H), 0.79 (d, J = 7.0 Hz, 3H), 0.62 (d, J = 6.9 Hz, 3H);

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C NMR (75 MHz, CDCl3) δ 159.9 (C), 158.5 (C), 158.4 (C), 114.4 (C), 91.1

(CH), 90.6 (CH), 55.7 (CH3), 55.1 (CH3), 54.9 (CH3), 43.9 (CH), 40.1 (CH2), 37.4 (CH), 35.4 (CH2), 33.4 (CH), 28.4 (CH), 25.2 (CH2), 22.4 (CH3), 21.5 (CH3), 15.6 (CH3); MS (EI) m/z (rel intensity, %) 306 (M+, 41), 221 (100), 181 (65); HRMS (EI-TOF) m/z calcd for C19H30O3 306.2195, found 306.2196. Anal. Calcd for C19H30O3: C, 74.47; H 9.87. Found: C, 74.62; H 9.96. Two Other Procedures for Catalytic Hydrogenation of 1e. (1) 1e (600 mg, 2.34 mmol) and PtO2 (10%, 60 mg) in ethyl acetate (60 mL) were placed under atmospheric pressure of H2 at rt. The reaction mixture was stirred for 6 days. The catalyst was then removed by filtration, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc 98/2) to give 2e (230 mg, 38 %) as a mixture of three diastereoisomers with ratios of epimers 1S/1R (70/30) and atropisomers 1S,P/1S,M (87/13 in CDCl3). Preparative TLC (petroleum ether/EtOAc 97/3) separation gave after twice elution an enriched fraction in 1R-epimer: ratios of epimers 1S/1R (55/45) and atropisomers 1S,P/1S,M (87/13 in CDCl3). (2) 1e (100 mg, 0.55 mmol) and Pd/C (10%, 10 mg) in ethyl acetate (10 mL) were placed under 5 bars of H2 at rt. The reaction mixture was stirred for 24h. The catalyst was then removed by filtration, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether/CH2Cl2 95/5) to give 2e (39 mg, 39 %) as a mixture of three diastereoisomers with ratios of epimers 1S/1R (70/30) and atropisomers 1S,P/1S,M (87/13 in CDCl3). Other Procedures for the Synthesis of 2b,f-h. Synthesis of (1S)-2b from (1S)-2a: A suspension of (1S)-2a (150 mg, 0.49 mmol) as a mixture of two rotamers 1S,P/1S,M (46/54 in CD3OD), Me2SO4 (0.13 mL, 154 mg, 1.22 mmol) and anhydrous K2CO3 (135 mg, 0.98 mmol) in Me2CO (5 mL) was stirred under reflux for 4h. The reaction was filtered and evaporated under reduced pressure to give a residue ACS Paragon Plus Environment

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that was purified by silica gel column chromatography (petroleum ether/ethyl acetate 99/1) to yield the di-ether as a solid (158.3 mg, 97 %). Ac2O (2.25 mL) was then added to a solution of the di-ether (128 mg, 0.38 mmol) in pyridine (1.5 mL) at rt under a N2 atmosphere, and the whole was stirred at 80°C overnight. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/EtOAc 90/10) to yield (1S)-2b (71 mg, 49%) as a mixture of two rotamers 1S,P/1S,M (40/60 in CDCl3). Synthesis of Ether 2f from 2e: A suspension of 2e (94 mg, 0.36 mmol) as a mixture of three diastereoisomers with ratios of epimers 1R/1S (30/70) and atropisomers 1S,P/1S,M (85/15 in CDCl3), Me2SO4 (0.08 mL, 92 mg, 0.75 mmol), and anhydrous K2CO3 (143 mg, 0.90 mmol) in Me2CO (5 mL) was stirred under reflux for 4h. The reaction was filtered and evaporated under reduced pressure to give a residue that was purified by silica gel column chromatography (petroleum ether) to yield 2f (86 mg, 86%) as a mixture of three diastereoisomers with ratios of epimers 1R/1S (30/70) and atropisomers 1S,P/1S,M (85/15 in CDCl3). Synthesis of Acetate 2g from 2e: Ac2O (1.5 mL) was added to a solution of 2e (80 mg, 0.25 mmol) as a mixture of three diastereoisomers with ratios of epimers 1R/1S (13/87) and atropisomers 1S,P/1S,M (85/15 in CDCl3) in pyridine (1 mL) at rt under a N2 atmosphere, and the whole was stirred at 80°C overnight. The reaction mixture was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography to give acetate 2g (63 mg, 83%) as a mixture of three diastereoisomers with ratios of epimers 1R/1S (13/87) and atropisomers 1S,P/1S,M (80/20 in CDCl3). Synthesis of Pivalate 2h from 2e: PivCl (1 mL) was added to a solution of 2e (80 mg, 0.25 mmol) as a mixture of three diastereoisomers with ratios of epimers 1R/1S (13/87) and atropisomers 1S,P/1S,M (85/15 in CDCl3) in pyridine (1 mL) at rt under a N2 atmosphere, and the whole was stirred at 80°C overnight. The reaction mixture was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (petroleum ether/CH2Cl2 90/10) to give pivalate 2h (69 mg, 66%) as a mixture of three diastereoisomers with ratios of epimers 1R/1S (13/87) and atropisomers 1S,P/1S,M (73/27 in CDCl3). ACS Paragon Plus Environment

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Acknowledgment. We thank C. Petermann and C. Machado for spectroscopic recordings (NMR and MS, respectively), S. Lanthony for microanalysis and HPLC technical assistance, and MF thanks the MENRT for a PhD fellowship. We are also grateful to P3M platform (MaSCA) for computational facilities and PlAneT platform for high field NMR facilities. Supporting Information Available. 1H and 13C NMR spectra of compounds 2a-i; NOESY spectra of 1e and 2b,e; VT 1H NMR spectra of 1e and 2b,d,e,h,i; VT-2D EXSY spectra of 2b,e,f; Eyring plots data of 2b,e,f. HPLC chromatogram of 2e, computational data of 2b,e,f. This material is available free of charge via the Internet at http://pubs.acs.org. (1) (a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley-Interscience: New York, 1994. (b) Wolf, C. Dynamic Stereochemistry of Chiral Compounds; Royal Society of Chemistry: Cambridge, U.K., 2008. (2) (a) Ǒki, M. Angew. Chem. 1976, 88, 67-96; Angew. Chem. Int. Ed. 1976, 15, 87-93. (b) Nakamura, M.; Ǒki, M. Bull. Chem. Soc. Jpn. 1980, 53, 2977-2980. (3) (a) Lomas, J. S.; Dubois, J. E. J. Org. Chem. 1976, 41, 3033-3034. (b) Lomas, J. S.; Anderson, J. E. J. Org. Chem. 1995, 60, 3246-3248. (c) Casarini, D.; Lunazzi, L.; Mazzanti, A. J. Org. Chem. 1997, 62, 3315-3323. (d) Wolf, C.; Pranatharthiharan, L.; Ramagosa, R. B. Tetrahedron Lett. 2002, 43, 85638567. (e) Casarini, D.; Coluccini, C.; Lunazzi, L.; Mazzanti, A. J. Org. Chem. 2005, 70, 5098-5102. (4) (a) Eto, M.; Yamaguchi, K.; Shinohara, I.; Ito, F.; Yoshitake, Y.; Harano, K. Tetrahedron 2010, 66, 898-903. (b) Murrison, S.; Glowacki, D.; Einzinger, C.; Titchmarsh, J.; Bartlett, S.; McKeeverAbbas, B.; Warriner, S.; Nelson, A. Chem. Eur. J. 2009, 15, 2185-2189. (c) Casarini, D.; Rosini, C.; Grilli, S.; Lunazzi, L.; Mazzanti, A. J. Org. Chem. 2003, 68, 1815-1820. (d) Boiadjiev, S. E.; Lightner, D. A. Tetrahedron: Asymmetry 2002, 13, 1721-1732. (e) Martin, H. J.; Drescher, M.; Kählig, H.; Schneider, S.; Mulzer, J. Angew. Chem. Int. Ed. 2001, 40, 3186-3188.


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(5) Ǒki, M. Acc. Chem. Res. 1990, 23, 351-356. (6) Berber, H.; Lameiras, P.; Denhez, C.; Antheaume, C.; Clayden, J. J. Org. Chem. 2014, 79, 60156027. (7) (a) Muhammad, I.; Li, X.-C.; Jacob, M. R.; Tekwani, B. L.; Dunbar, D. C.; Ferreira, D. J. Nat. Prod. 2003, 66, 804-809. (b) Ben-Shabat, S.; Hanuš, L. O.; Katzavian, G.; Gallily, R. J. Med. Chem. 2006, 49, 1113-1117. (8) (a) Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPlante, S. R. Angew. Chem. Int. Ed. 2009, 48, 6398-6401. (b) LaPlante, S. R.; Edwards, P. J.; Fader, L. D.; Jakalian, A.; Hucke, O. ChemMedChem 2011, 6, 505-513. (c) LaPlante, S. R.; Fader, L. D.; Fandrick, K. R.; Fandrick, D. R.; Hucke, O.; Kemper, R.; Miller, S. P. F.; Edwards, P. J. J. Med. Chem. 2011, 54, 7005-7022. (9) (a) Kane, V. V.; Martin, A. R.; Jaime, C.; Ŏsawa, E. Tetrahedron 1984, 40, 2919-2927. (b) Jaime, C.; Ŏsawa, E. J. Mol. Struct. 1985, 126, 363-380. (10) (M,P) nomenclature can also be used in sp2-sp3 axial chirality, and the conformers are rotational diastereoisomers here. For clarity in the labelling of the compounds, (R,S) nomenclature is used to designate diastereoisomers (or epimers) resulting from the center of chirality (C1) and (M,P) nomenclature to rotational diastereoisomers. Likewise, the other centers of chirality (C3, C4) are not indicated in their numeral names. (11) Delaye, P.-O.; Lameiras, P.; Kervarec, N.; Mirand, C.; Berber, H. J. Org. Chem. 2010, 75, 25012509. (12) A second elution of the TLC along a perpendicular axis showed cross-spots indicating interconversion of (1S)-2e atropisomers on the plate over a period of minutes. 2D TLC analysis showed also that interconversion occurs between the more and the less polar spots (see Rf values in the Experimental Section); and the third spot ((1R)-2e) is very close to the less polar spot (almost ACS Paragon Plus Environment

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overlapped), which was also confirmed by HPLC analysis (see chromatogram in the Supporting Information. (13) (a) Tietze, L. F.; Schuster, H. J.; von Hof, J. M.; Hampel, S. M.; Colunga, J. F.; John, M. Chem. Eur; J. 2010, 16, 12678-12682. (b) Rate constants were obtained by using EXSYCalc program: J. C. Cobas, M. Martin-Pastor, EXSYCalc Version 1.0, Mestrelab Research; see in the Supporting Information for details. (14) (a) Sandström J. Dynamic NMR Spectroscopy; Academic Press: New York, 1982. (b) ShananAtidi, H.; Bar-Eli, K.H. J. Phys. Chem. 1970, 74, 961-963. (15) For computational details, see in the Supporting Information. (16) (a) The experimental entropies of activation of (1R)-2e,f conformers are unusually large in absolute value, in the range of -127.7 to -193.6 Jmol-1K-1, as shown in Table S3 in the Supporting Information. These values should be almost zero for such a process whose transition state does not involve either bond making or breaking. They may include some intractable systematic errors originate from T and k values measured by VT-NMR EXSY technique: Binsch, G. Top. Stereochem. 1968, 3, 97192. (b) For review articles that demonstrate that not negligible ∆S≠ values in conformational processes are invariably a consequence of inaccurate measurements, see also: Casarini, D.; Lunazzi, L.; Mazzanti, A. Eur. J. Org. Chem., 2010, 11, 2035-2056. (17) (a) Johnson, E. R.; Keinan, S.; Mori-Sanchez, P.; Contreras-Garcia, J.; J. Cohen, A.J.; Yang, W. J. Am. Chem. Soc. 2010, 132, 6498-6506. (b) Contreras-Garcia, J.; Johnson, E. R.; Keinan, S.; Chaudret, R.; Piquemal, J-P.; Beratan, D. N.; Yang. W. J. Chem. Theory Comput. 2011, 7, 625-632.


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